Abstract Granulomas form as a conserved host response to a variety of inflammatory and infectious stimuli. As granulomas assemble, macrophages interdigitate and undergo a striking morphological transition, taking on an epithelioid appearance. The basis for this transformation and the consequences for disease are not fully understood. We have identified a conserved reprogramming of macrophages that underlies the assembly and stability of mycobacterial granulomas. Using a zebrafish model, we find that epithelial modules and structures are induced during granuloma formation and are critical for granuloma integrity. In this project we will 1) use long-term intravital imaging to assess key epithelial modules engaged by macrophages during granuloma formation and how disruption of the mycobacterial granuloma can lead to improved host outcome; 2) test the role of the IL-4/IL-13/Stat6 axis during macrophage reprogramming events; 3) based on RNA-seq analysis of macrophages isolated from infected animals, assess the role of the sonic hedgehog (Shh) pathway in granuloma formation, maintenance, and infection trajectory. Findings from this project will be translated into human disease. Overall, this proposal will test the hypothesis that, in a striking parallel to mesenchymal-to- epithelial transitions in cancer, macrophages draw on classical developmental signaling pathways to undergo an epithelial-like transition and construct the central structure of tuberculosis. A new perspective on this critical structure may have important implications for our understanding of disease progression and the design of new therapeutic approaches.